Breakthrough Medicines

The company’s lead investigational candidate, SYNT001, is quickly advancing in a wide range of autoimmune diseases. SYNT001 is a humanized monoclonal antibody engineered to have high affinity blockade of IgG and IgG immune complex interactions with FcRn. As a pipeline-in-a-product, SYNT001 demonstrates great potential to treat autoimmune diseases in dermatology, hematology, neurology and more.

PIPELINE

SYNT001 is currently being studied in patients with pemphigus (vulgaris or foliaceus), and in warm autoimmune hemolytic anemia. Additional indications are to be announced.

Target Indication

DISCOVERY

IND ENABLING

PHASE 1a

PHASE 1b/2a

PHASE 2b

PHASE 3

DERMATOLOGY

Pemphigus (Vulgaris and Foliaceus)

PHASE 1b/2a

Additional Indication TBA

PHASE 1a

HEMATOLOGY

Warm Autoimmune Hemolytic Anemia

PHASE 1b/2a

NEUROLOGY

Additional Indication TBA

PHASE 1a

Additional Indication TBA

PHASE 1a

Active Indication/ Ongoing study

Expansion Indications/ Study Not Yet Commenced

SYNT001: Broad Applicability in IgG-mediated Diseases

Syntimmune’s lead investigational candidate, SYNT001, holds strong promise to potentially transform patient care in IgG-mediated autoimmune diseases. There are important unmet needs in these diseases, including need for faster onset of action, more effective disease control, improved safety profile, steroid-sparing effect and more.

SYNT001 has been designed to optimally bind FcRn at both neutral and endosomic (acid) pH levels, thereby potently inhibiting the interaction of FcRn with IgG and IgG immune complexes.

As shown in the graphic below, SYNT001 blocks FcRn-mediated recycling of IgG to drive degradation of IgG within cells and rapidly reduce circulating IgG. SYNT001 is also predicted to block FcRn-mediated inflammatory cytokine release induced by immune complexes, as well as FcRn-mediated presentation of IgG-complexed antigens. This has the potential to prevent expansion of autoimmune responses by blocking FcRn-mediated activation of new autoreactive T cells and B cells.

In data from a Phase 1a single ascending dose investigational study of SYNT001 in healthy volunteers, SYNT001 data demonstrated a potent, dose-dependent and rapid reduction in total IgG and circulating immune complex levels to below a clinically meaningful threshold within five days. Reductions were seen in all IgG subtypes, with no effect seen on IgA, IgM or albumin levels. Based on animal models, SYNT001 is predicted to block FcRn’s role in antigen processing and presentation that can activate CD4+ and CD8+ T cells to produce inflammatory cytokines, which subsequently lead to increased levels of IgG production by B cells.

In preliminary results from a Phase 1b proof-of-concept investigational trial of SYNT001, data demonstrated a rapid reduction in IgG and circulating immune complex levels, as well as an acceptable safety and tolerability profile similar to that observed in the Phase 1a study.

Pemphigus is an autoimmune disease characterized by cutaneous and/or mucus membrane blisters that easily break, resulting in painful blistering and skin erosions. Patients are typically diagnosed between the ages of 40 and 60, with children rarely developing the disease. The two most common forms of the disease are pemphigus vulgaris and pemphigus foliaceus, constituting approximately 80% and 20% of all cases.

The hallmark of pemphigus is cell surface-bound pathogenic IgG within the epidermis which directly contributes to the formation of blisters and skin erosions. Corticosteroids are typically used as first-line therapy while anti-CD20 mAbs, such as rituximab, are being used with increasing frequency. Currently available therapies are limited by associated toxicities (both acute and chronic), delayed onset of action, high frequency of relapse, and patient inconvenience.

In preliminary results from a Phase 1b proof-of-concept trial of SYNT001 in patients with pemphigus vulgaris or pemphigus foliaceus, SYNT001 data showed safety and tolerability profiles similar to that observed in the Phase 1a study. A rapid and consistent reduction in total IgG and immune complex levels was observed. The effect was reversible upon cessation of treatment. There were no severe study drug-related adverse events.

Warm autoimmune hemolytic anemia is a chronic disease caused by pathogenic IgG antibodies that react with and cause the destruction of red blood cells at normal body temperature. The pathogenic antibodies may occur spontaneously, in association with certain disorders or after the use of certain drugs. The disease may develop gradually, or can have a rapid onset with profound, life-threatening anemia. Severe complications can include jaundice, dyspnea, syncope, angina, tachycardia and heart failure.

There are no FDA-approved treatments for warm autoimmune hemolytic anemia other than corticosteroids, which can cause significant adverse effects with long-term use.

SYNT002: CLEARANCE OF ALBUMIN-BOUND TOXINS

FcRn plays a key role in regulating albumin, an abundant blood plasma protein that binds to toxins, drugs and hormones and transports them through the bloodstream to be excreted. A pivotal insight from the groundbreaking work of the Syntimmune team is that FcRn binds albumin and protects it from degradation in the liver. FcRn thus can maintain levels of albumin and albumin-bound toxins in the bloodstream.

In preclinical models, SYNT002 blocked albumin’s interactions with FcRn, thereby showing the potential to facilitate the clearance of albumin-bound toxins and protect organs such as the liver from toxicity. Syntimmune is engaged in preclinical investigation of SYNT002 and a set of related compounds, including peptide mimetics, to demonstrate their potential in numerous diseases.